Definitive therapy for squamous cell carcinoma of the anus with synchronous distant metastases
Karen Wind, Department of Clinical Medicine
E. Serup-Hansen, Department of Oncology, Herlev and Gentofte Hospital; L. Riber, Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark; BM.
Havelund, Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark; C. Kronborg, Danish Centre for Particle Therapy, Aarhus University Hospital; A.
Jakobsen, Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark; KLG. Spindler KLG, Department of Experimental Clinical Oncology, Aarhus University Hospital
Introduction: Synchronous metastatic squamous cell carcinoma of the anus (mSCCA) is rare, and little evidence exists on potential curative treatment options. The aim of this study was to present outcome of a nationwide cohort of patients with synchronous mSCCA treated with a definitive treatment strategy.
Materials and Methods: Patients with synchronous mSCCA treated with ICT and definitive RT between 2000 and 2018 were included. Pre-treatment characteristics, treatment- and outcome data were collected from medical records. The Kaplan-Meier method was used to present survival functions.
Results: Nineteen patients with synchronous mSCCA were identified. Location of distant metastases were liver (n=5), lung (n=1), bone (n=1), skin (n=3), and metastatic lymph nodes (LN) (n=9). Patients were treated with intensified ICT consisting of cisplatin, 5- flourouracil, leucovorin and ifosfamide followed by definitive RT. Prescribed RT doses to tumour and pathological LN were 50.4-64 Gy in 28-32 fractions and 49.9-51.2 Gy to the elective clinical target volume. Four patients underwent additional local treatment for distant metastases. On ICT alone, the overall objective local tumour response was 88%
with 31% achieving complete local tumour response. Median follow-up time was 4.5 years (range 0.9-.17). Overall survival at 3- and 5-years was 72% and 55%, respectively, and 3- and 5-year disease-free survival was 47% and 41%, respectively.
Conclusions: Selected patients with synchronous mSCCA can be treated with a definitive strategy hereby shifting patients from a palliative to a curative treatment intent.
Prospective international trials are needed to investigate this approach further.
Keywords: Oncology, Other, Other
OPTIMISE - OPTIMIzation of treatment SElection and follow up in
oligometastatic colorectal cancer - a ctDNA guided phase II randomized approach
Louise Callesen, Department of Clinical Medicine
L.B. Callesen, Department of Oncology, Aarhus University Hospital; T. F. Hansen,
Department of Oncology, Vejle Hospital; R.F. Andersen, Department of Biochemistry and Immunology, Vejle Hospital; N. Pallisgaard, Department of Pathology, Zealand University Hospital; S. Kramer, Department of Nuclear Medicine & PET-Centre, Aarhus University Hospital; S. Schlander, Department of Radiology, Aarhus University Hospital; S. Rafaelsen, Department of Radiology, Vejle Hospital; A.K. Boysen, Department of Oncology, Aarhus University Hospital; L.H. Jensen, Department of Oncology, Vejle Hospital; A. Jakobsen, Department of Oncology, Vejle Hospital; K.G. Spindler, Department of Oncology, Aarhus University Hospital
Background: Oligometastatic colorectal cancer (CRC) can be cured from treating a single or few local metastases. Some patients obtain long-term survival, whereas others show an aggressive biological behavior with early recurrence and systemic dissemination despite the use of adjuvant chemotherapy (CT). Due to limited evidence, there is no clear
consensus on the use of CT in relation to local treatment. A pilot study demonstrated, that presence of ctDNA in plasma after curative treatment for oligometastatic CRC indicates a poor prognosis. We aim to investigate the clinical utility of ctDNA-guided treatment in oligometastatic CRC.
Materials and methods: An open label 1:1 randomized phase II exploratory study investigating use of ctDNA-guided therapy compared to standard of care after local treatment for metastatic CRC. Circulating free DNA will be analyzed for CRC specific mutations by a digital droplet PCR panel and for tumor-specific hypermethylation by a methylation assay. ctDNA positivity will lead to escalation of CT. ctDNA negativity will based on shared decision making lead to de-escalation.
Results: This study will demonstrate the feasibility of patient inclusion, rate of imaging detected residual disease, rate of ctDNA positivity and shared decision making in ctDNA- guided therapy for oligometastatic CRC. It will lead to a larger multicenter randomized study, investigating the clinical utility of ctDNA-guided treatment.
Conclusion: Oligometastatic CRC can be cured, but with a high risk of recurrence.
Currently, clinical indicators for optimal selection of post-treatment CT are missing. We investigate ctDNA-guided treatment to optimize use of CT and hereby outcome.
Keywords: Oncology, Other, Other
Plasma proteins as biomarkers for response to immunotherapy in non-small cell lung cancer patients
Simone Stensgaard, Department of Clinical Medicine, Department of Clinical Biochemistry
A. Thomsen, Department of Clinical Biochemistry; J.G. Dissing, Department of Clinical Biochemistry; P. Meldgaard, Department of Oncology; B.S. Sørensen, Department of Clinical Biochemistry
Background: Immunotherapy development has improved survival for advanced-stage non-small cell lung cancer (NSCLC) patients. Pembrolizumab, an immune checkpoint inhibitor, targets the PD-1 signaling axis and has produced durable clinical response.
Despite PD-L1 expression being used as a biomarker for treatment eligibility, its predictive value remains ambiguous. Using blood samples from NSCLC patients, we aimed to identify biomarkers with higher predictive value for therapeutic efficacy.
Materials and methods: A cohort of 42 advanced NSCLC patients receiving first- or second-line pembrolizumab treatment were included. Blood samples were collected before treatment and again three and six weeks after treatment initiation. The blood samples were analyzed using the proteomic multiplex platform Olink. We investigated the expression of 92 plasma proteins known to be associated with immuno-oncology.
Results: Patients were stratified by progression-free survival (PFS), and plasma protein expression was compared between the two groups. At all three time points (baseline, and at three and six weeks after treatment initiation) Fas ligand was associated with favorable PFS (p=0.0003, p=0.0134 and p=0.0039). Patients with the highest quartile Fas ligand expression at baseline had significantly longer PFS (p=0.0077) than patients with lower Fas ligand expression.
Conclusion: This study sheds new light on the possibilities of plasma proteins as candidates for predictive biomarkers for immunotherapy response or as indicators of resistance
mechanisms.
Keywords: Oncology, Other, Other
Early response to chemotherapy as predictor of locoregional and distant failure in NSCLC
Marie Tvilum, Department of Clinical Medicine, Dept. of Oncology
M. TVILUM, Dept. Of Oncology, Aarhus University Hospital, M.M. KNAP, Dept. Of Oncology, Aarhus University Hospital, C.M. LUTZ, Dept. Of Medical Physics, Aarhus University Hospital, L. HOFFMANN, Dept. Of Medical Physics, Aarhus University Hospital, A.A. KHALIL, Dept. Of Oncology, Aarhus University Hospital, A. HARALDSEN, Dept. Of Clinical Medicine - Nuclear Medicine and PET, Aarhus University Hospital, M. ALBER, Dept. Of Radiation Oncology, Heidelberg University Clinic, Germany, C. GRAU, Dept of Oncology and Danish Center for Particle Therapy, Aarhus University Hospital, Denmark, H.H. Schmidt, Dept. Of Oncology, Aarhus University Hospital, M. Kandi, Dept. Of Oncology, Aarhus University Hospital, M.I. Holt, Dept. Of Oncology, Aarhus University Hospital, L.S. Mortensen, Dept. Of Oncology, Aarhus University Hospital, A. APPELT, Institute of Medical Research at St James’s, University of Leeds, United Kingdom, D.S. MØLLER, Dept. Of Medical Physics, Aarhus University Hospital
PURPOSE/OBJECTIVES
Combined chemo-radiotherapy (cRT) is standard of care for patients with locally
advanced non-small cell lung cancer (LA-NSCLC). This study evaluates the early tumour response after chemotherapy and its prognostic value in predicting pattern of failure for LA-NSCLC-patients.
MATERIAL AND METHODS
Patients with LA-NSCLC treated with curative intended cRT (2012-2019) were
retrospectively reviewed (n=188). Patients had diagnostic PET/CT-(dPC) and planning PET/CT (pPC)-scans, between which they received platinum-based chemotherapy.
Volume, sphericity and SUVpeak for the gross tumour volume were investigated on dPC and pPC. Failure was characterized as loco-regional (LR), distant metastasis (M) or simultaneous (LR+M). Two multivariate competing risk analyses (Fine-Gray model) were performed.
RESULTS
Median follow-up was 33 months. Median decrease in GTV-T volume and SUVpeak were 19.1% and 32.7%, respectively. In Model 1, squamous cell carcinomas (SCC) presented a significantly lower risk of M failure (SHR=0.246 [0.0887-0.684], p<0.01), and higher risk of LR failure (SHR=2.15 [1.09-4.21], p=0.026) compared to adenocarcinomas (AC). In Model 2, SUVpeak at diagnosis was the only significant predictor of LR failure (SHR=1.07 [1.02-1.13], p<0.01), while histology was still a significant predictor of M failure (SHR=0.259 [0.0970- 0.694], p<0.01, SCC). Analysis on subgroups (histology, SUVpeak above and below
median) illustrated that ACs with high SUVpeak are more prone to failure than ACs with low SUVpeak.
CONCLUSION
Histology and tumour SUVpeak were significant predictors of LR failure in a multivariate model based on 188 LA-NSCLC patients treated with cRT.
Keywords: Oncology, Respiratory system, Other
Time-resolved dose rate measurements in pencil beam scanning proton FLASH therapy
Eleni Kanouta, Department of Clinical Medicine
E. Kanouta, Danish Centre for Particle Therapy, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University; P. Poulsen, Danish Centre for Particle Therapy, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University; G.
Kertzscher, Danish Centre for Particle Therapy, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University; M. Sitarz, Danish Centre for Particle Therapy, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University; J. Johansen, Danish Centre for Particle Therapy, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University
Introduction: It has been found that delivering the dose in radiotherapy with high dose rates leads to normal tissue sparring while maintaining the tumor response (FLASH therapy). To ensure that high enough dose rate is obtained, a detector system for time- resolved dose rate measurements was developed. The detector was used in pre-clinical pencil beam scanning proton FLASH studies to measure the instantaneous dose rate during mouse irradiations.
Methods: The detector system consisted of four probes and measured the dose rate every 20 us. Prior to the mice studies, the probes were cross-calibrated against an ionization chamber that was irradiated simultaneously with the probes using a range of dose rates. A calibration curve was produced linking the probe signal (in voltage) to the absolute
instantaneous dose rate (in Gy/s). The calibrated probes were then used to measure the instantaneous dose rates during mouse experiments.
Results: For each probe, the instantaneous dose rate as function of measured detector signal was modelled with a third-degree polynomial function. The dose rate in the mouse irradiations was consistent with the dose rates recorded by machine log-files of the treatments with a root-mean-square difference of 13Gy/s across a wide range of instantaneous dose rates up to 1000Gy/s.
Conclusion: A detector system for direct measurements of the instantaneous dose rate was developed and calibrated in a wide range of dose rates. The calibrated system was
successfully used in vivo in mouse irradiations, enabling time-resolved dose rate measurements in pre-clinical proton FLASH studies.
Keywords: Oncology, Other, Other
Deciphering metastatic cancer biology.
A panel-based study
Ditte Sigaard Christensen, Department of Clinical Medicine, MOMA
Ahrenfeldt, J, Department of Molecular Medicine Birkbak, N., Department of Molecular Medicine
Metastatic disease is responsible for 90% of all cancer deaths. Understanding the process of how primary tumours achieve metastatic potential is of great importance and
paramount to the development of precision medicine that may limit the aggressive distant spread of metastatic cancer. We wish to investigate if potential metastatic gate-keeper mutations exist.
We analysed panel-based DNA sequencing datasets from the GENIE (Genomics Evidence Neoplasia Information Exchange) project. Analyses were performed on 174 shared genes and 37,791 patients were included. Using bioinformatic tools, we compared genomic alterations in primary versus metastatic samples.
We found a higher tumour mutation burden and increased levels of chromosomal instability for metastatic samples compared to primary. Overall, TP53, MYC and CDKN2A were the most significantly enriched genes in metastatic cancer. Notably, we also
identified several genes as significantly depleted in metastatic cancer. These particularly include ARID1A and PIK3CA.
We demonstrate how the power of large datasets can be utilised to make novel
inferences on cancer biology. We identified both enrichments and depletions of specific alterations in metastatic disease potentially revealing how certain driver gene
combinations associate with cancer progression more commonly than others. However, no prevalent differences were identified, and considering the large number of patients
included, it might suggest that the metastatic process is driven less by new acquired metastatic features, but more by a non-cancer feature such as inflammation in the surrounding tissue.
Keywords: Oncology, Cell biology, Other
Characteristics of Danish patients with pulmonary sarcoidosis
Janne Møller, Department of Clinical Medicine
E. Bendstrup, Department of Respiratory Diseases and Allergy, AUH O.Hilberg, Department of Medicine, Lillebaelt Hospital, Medicine, Vejle
Background and aim: Systematic data registration in sarcoidosis is warranted in order to phenotype patients with sarcoidosis and to enhance the understanding of the disease variability that differs among ethnic groups. The aim was to characterize a Danish cohort with pulmonary sarcoidosis at the time of diagnosis.
Methods: Patients diagnosed with sarcoidosis from January 2018 to August 2021 were included. Data on patient demographics, family history, symptoms, comorbidities, radiology and pathology was registered.
Results: In august 2021, 128 patients, all Caucasians (38% women) were included. Mean age at inclusion were 47 years. Five patients (4%) reported a first degree relative with sarcoidosis. Dyspnea and cough were reported in 52 (41%) and 47 (37%) of patients.
Comorbidities were present in 47% with hypertension being most prevalent. Most patients never smoked (63%). In 91 patients (71%) the diagnosis was verified by biopsy. Mean BAL lymphocyte count from 81 patients was 26% and mean CD4/CD8 ratio in 70 patients was 9.3. Distribution of Scadding stages on chest x ray (n=119) were: 0: 25%, I: 48% II: 24%, III:
5%, IV: 3%. Forced vital capacity was normal in 90% (n=123), mildly impaired (FVC 70-79%) in 7% (n=9) and moderately impaired (FVC 50-69%) in 2% (n=3). Diffusion capacity (n=99) was normal in 37(55%), mildly impaired (60-79%) in 32 % (n=32) and moderate impaired (40–60%) in 5% (n=5).
Conclusions: Danish sarcoid patients are predominantly males, and older at diagnosis compared to a previous Danish cohort. The majority had mild pulmonary disease at diagnosis according to Scadding stage and pulmonary function test.
Keywords: Respiratory system, Inflammation, Other